There exists a fundamental gap in understanding how CD8+ T cells, which target intracellular pathogens, protect against pathogens like Yersinia, which exist extracellularly. The candidate's long-term scientific goal is to understand mechanisms used by CD8+ T cells to recognize and eliminate Yersinia and mechanisms used by the bacteria to evade immune recognition and clearance. The objective of proposed research is to determine how T cell- and bacterial-induced apoptosis influences Yersinia infection outcomes. The central hypothesis is that the pro-apoptotic factors expressed by host and pathogen, specifically perforin from CD8+ T cells and YopJ from Yersinia, limit bacterial infection by inducing apoptosis of Yersinia-associated host cells and flagging them for phagocytic removal. Guided by strong preliminary data, two specific aims will test this hypothesis: 1) determine the contribution of perforin to CD8+ T cell-mediated elimination of host cell-associated Yersinia; and 2) determine how modulation of apoptosis by genetic or chemical manipulation influences Yersinia infection. Under the first aim, Yersinia challenge of mice with perforin-sufficient or -deficient antigen-specific CD8+ T cells will address if perforin-mediated apoptosis is required for CD8+ T cell-dependent protection. In the second aim, the consequence of genetic or chemical manipulation of apoptosis in vivo for Yersinia infection will be examined. The approach is innovative, because it manipulates both host and pathogen processes to reveal host-protective actions. The proposed work is significant, because it will advance understanding of host responses to Yersinia and suggest ways to improve current vaccines to maximally stimulate Yersinia-specific protective immunity. This work will also provide a foundation for establishing the candidate's independent research program. The candidate's immediate career goal is to successfully transition from postdoctoral fellow to assistant professor and independent researcher studying host responses to Yersinia. Her long-term career goal is to direct an independent and prolific research program studying host-pathogen interactions as tenured faculty at a leading academic institution. To achieve these goals, in addition to executing the research described above, the candidate will utilize a mentoring committee of established scientists to help develop the candidate's research program to its full potential, to speed the candidate's progression towards publication of the research, and hone the candidate's grantsmanship skills. Thus, the proposed research and career development plans fulfill the NIAID's mission to identify mechanisms of infectious agent pathogenesis and protective host responses and to support junior investigators at early stages of their careers. The proposed studies focus on important and under-investigated areas of cell-mediated immune responses to the bacteria pathogen Yersinia. They have the potential to reveal novel mechanisms of host resistance to infection. The proposed research has relevance to human health, because it will yield information that can be used to improve vaccines and other treatment strategies against pathogens like Yersinia, with the goal of protecting hosts and preventing disease.